This invention relates to a process for preparing 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols and 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-5,5xe2x80x2-dihalo-2,2xe2x80x2-biphenols.
Substituted biphenols such as 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol; 3,3xe2x80x2,4,4xe2x80x2,5,5xe2x80x2,6,6xe2x80x2-octaalkyl-2,2xe2x80x2-biphenols; 3,3xe2x80x2,5,5xe2x80x2,6,6xe2x80x2-hexaalkyl-2,2xe2x80x2-biphenols; 3,3xe2x80x2,5,5xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol; 3-alkyl-5,5xe2x80x2,6,6xe2x80x2,7,7xe2x80x28,8xe2x80x2-octahydro-2,2xe2x80x2-binaphthol; 3,3xe2x80x2-dialkyl-5,5xe2x80x2,6,6xe2x80x2,7,7xe2x80x28,8xe2x80x2-octahydro-2,2xe2x80x2-binaphthol and 3,3xe2x80x26,6xe2x80x2-tetralkyl-5,5xe2x80x2-dihalo-2,2xe2x80x2-biphenol are compounds that can be used to make phosphorus-based catalyst ligands. Such ligands include phosphines, phosphinites, phosphonites, and phosphites. Mono(phosphorous) ligands are compounds that contain a single phosphorus atom which serves as a donor to a transition metal, while bis(phosphorus) ligands, in general, contain two phosphorus donor atoms and typically form cyclic chelate structures with transition metals.
In general, biphenols can be made by the oxidative coupling of (mono)phenols, but often other types of products, such as ketones, are obtained, and/or overall yields are poor for other reasons.
Phenols can be oxidatively coupled to make the corresponding biphenols by the use of a variety of oxidizing agents, such as nitric acid, ferric chloride, potassium ferricyanide, chromic acid, 2,3-dichloro-5,6-dicyanobenzoquinone and di-t-butyl peroxide. 2,2xe2x80x2-Dihydroxy-3,3xe2x80x2-di-isopropyl-6,6xe2x80x2-dimethylbiphenyl can be prepared from 2-isopropyl-5-methyl-phenol with 2,3-dichloro-5,6-dicyanobenzoquinone or di-t-butyl peroxide. See Tetrahedron, 1875, 1971 and J. Chem. Soc., Perkin Trans. II, 587, 1983. Some of the oxidants and/or co-catalysts involve the use of relatively expensive and/or explosive (peroxides) compounds, which pose disadvantages for large scale commercial use.
Phenols can also be oxidatively coupled using a combination of a transition metal catalyst and an oxidizing agent such as persulfate anion or oxygen. See U.S. Pat. Nos. 6,077,979; 4,139,544; 4,132,722; 4,354,048; and 4,108,908. See also J. Org. Chem. 1984, 49, 4456 and J. Org. Chem. 1983, 48, 4948. The cited patents disclose the use of oxygen as an oxidizing agent with various copper complexes as catalysts (copper chromite; copper acetate with sodium mercaptoacetate; copper acetate with pentasodium/diethylenetriaminepentacetate; copper acetate with 1,3-diamino-2-hydroxypropane-tetracetic acid). The examples in the patents disclose the use of 2,6-disubstituted phenol or 2,4-di-tert-butylphenol.
The use of copper amine catalysts, with oxygen as an oxidizing agent, has been described in connection with the oxidative coupling of 2,4-di-tert-butylphenol, 2-methyl-4-tert-butylphenol, 2-chlor-4-tert-butylphenol and 4-tert-butylphenol. See J. Org. Chem. 1984, 49, 4456 and J. Org. Chem. 1983, 48, 4948.
There is a continuing need in the art for methods for making with decent yields substituted biphenols suitable for making phosphorous-based catalyst ligands.
In its first aspect, the present invention is a process for making a compound of the formula I 
wherein
R1 is C1 to C10 primary or secondary alkyl or cycloalkyl,
R2 is C1 to C10 primary or secondary alkyl or cycloalkyl, and
X is H, Cl, Br, or I,
comprising:
(1) when X is Cl
(a) chlorinating a compound of the formula II 
xe2x80x83at the 4-position thereof to produce a compound of the formula III 
xe2x80x83wherein X is Cl,
(b) oxidatively coupling the compound of the formula III wherein X is Cl to produce a compound of the formula I wherein X is Cl;
(2) when X is H
(a) chlorinating a compound of the formula II at the 4-position thereof to produce a compound of the formula III wherein X is Cl,
(b) oxidatively coupling the compound of the formula III wherein X is Cl to produce a compound of the formula I wherein X is Cl, and
(c) dechlorinating the compound of the formula I wherein X is Cl to produce a compound of the formula I wherein X is H; or
(3) when X is Br or I
(a) chlorinating a compound of the formula II at the 4-position thereof to produce a compound of the formula III wherein X is Cl,
(b) oxidatively coupling the compound of the formula III wherein X is Cl to produce a compound of the formula I wherein X is Cl,
(c) dechlorinating the compound of the formula I wherein X is Cl to produce a compound of the formula I wherein X is H, and
(d) substituting Br or I, respectively, for H at the 5 and 5xe2x80x2 positions of the compound of the formula I wherein X is H.
In its second aspect, the present invention is a process for making a compound of the formula IV 
wherein
R1 is C1 to C10 primary or secondary alkyl or cycloalkyl,
R4 is C1 to C10 primary or secondary alkyl or cycloalkyl, and
X is H, Cl, Br, or I
comprising:
(1) when X is H
(a) alkylating a compound of the formula V 
xe2x80x83at the 4-position thereof to produce a compound of the formula VI 
xe2x80x83wherein R3 is C4 to C20 tertiary alkyl,
(b) oxidatively coupling the compound of the formula VI to produce a compound of the formula VII 
(c) dealkylating a compound of the formula VII to produce a compound of the formula IV wherein X is H; or
(2) when X is Cl, Br, or I
(a) alkylating a compound of the formula V at the 4-position thereof to produce a compound of the formula VI,
(b) oxidatively coupling the compound of the formula VI to produce a compound of the formula VII,
(c) dealkylating a compound of the formula VII to produce a compound of the formula IV wherein X is H, and
(d) substituting Cl, Br, or I, respectively, for H at the 5 and 5xe2x80x2 positions of the compound of the formula IV wherein X is H.
In its third aspect, the present invention is a process for making a compound of the formula I 
wherein
R1 is C1 to C10 primary or secondary alkyl or cycloalkyl,
R2 is C1 to C10 primary or secondary alkyl or cycloalkyl, and
X is H,
comprising:
(a) oxidatively coupling a compound of the formula III 
xe2x80x83wherein X is Cl, to produce a compound of the formula I wherein X is Cl, and
(b) dechlorinating the compound of the formula I wherein X is Cl to produce a compound of the formula I wherein X is H.
In another aspect the present invention is a compound selected from the group consisting of 3,3xe2x80x2,6,6xe2x80x2-tetramethyl-2,2xe2x80x2-biphenol, and 3,3xe2x80x2-di-isopropyl-6,6xe2x80x2-dimentyl-2,2xe2x80x2-biphenol.
The first aspect of the present invention provides a process for preparing 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol, comprising (1) substituting chlorine for hydrogen at the 4-position of 2,5-dialkylphenol, (2) oxidatively coupling the resulting 2,5-dialkyl-4-chloro-phenol, and (3) removing chlorine from the resulting compound. The second step is carried out by analogy with the methods of Sartori, et al (Tetrahedron, 1992, 48, 9483), but using the free phenol rather than its dichloroaluminate derivative. The three steps of the process are shown below. 
wherein R1 is C1 to C10 primary or secondary alkyl or cycloalkyl; and R2 is C1 to C10 primary or secondary alkyl or cycloalkyl.
Preferred R1 are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, cyclohexyl, and cyclopentyl. Preferred R2 are methyl and ethyl. The alkyl groups at the 2- and 5-postions may be the same or different.
In the first step of the process, a 2,5-dialkylphenol can be reacted with a chlorinating agent, such as chlorine or sulfuryl chloride, preferably in the presence of 1 to 10 mol % of a catalyst such as aluminum chloride or a diaryl sulfide such as diphenyl sulfide or a mixture thereof. See Watson, J. Org. Chem., 1985, 50, 2145. The reaction may be conducted neat (without a solvent) or in a medium such as dichloromethane, chlorobenzene, or other inert solvent at a temperature between xe2x88x9230 and 60xc2x0 C., preferably at about 25xc2x0 C. The reaction is typically performed at or about atmospheric pressure for ease of operation.
In the second step of the process, the resulting 2,5-dialkyl-4-chlorophenol can be oxidatively coupled to give the corresponding dimeric chlorophenols (5,5xe2x80x2-dichloro-3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol). The preferred method for oxidative coupling of the chlorinated phenols is by the use of an iron(III) salt, preferably ferric chloride, in a suitable polar, aprotic solvent such as dichloromethane or nitromethane, preferably nitromethane at temperature between 0xc2x0 C. and 60xc2x0 C., preferably about 35xc2x0 C. The product is isolated by dilution with water and filtration.
In the third step of the process, dechlorination of 5,5xe2x80x2-dichloro-3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols can be accomplished by hydrogenolytic reduction to provide the required 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols. The reduction is carried out in the presence of hydrogen gas, preferably at pressures between 1 and 50 atmospheres and temperature between 5xc2x0 and 80xc2x0 C., and a formate salt, such as sodium formate, and Raney(copyright) nickel or palladium catalyst such as palladium hydroxide on carbon. If a palladium catalyst is used, the reaction is generally carried out in a protic solvent such as methanol, containing 1.0 to 4.0 equivalents of an amine such as triethylamine to absorb the hydrogen chloride produced in the reaction.
The second aspect of the present invention provides a process for preparing a compound of the formula IV, comprising (1) substituting a tertiary alkyl group for hydrogen at the 4-position of 2,5-dialkylphenol, (2) oxidatively coupling the resulting 2,5-dialkyl-4-tert-alkyl-phenol, and (3) removing the tertiary alkyl group from the resulting compound. The three steps of the process are shown below. 
wherein R1 is C1 to C10 primary or secondary alkyl or cycloalkyl; R4 is C1 to C10 primary or secondary alkyl or cycloalkyl; and R3 is C4 to C20 tertiaryl alkyl.
In the first step of the process, a 2,5-dialkylphenol can be reacted with a tert-alkyl halide in the presence of a Lewis Acid catalyst, such as zinc chloride or aluminum chloride, to give a 2,5-dialkyl-4-tert-alkylphenol. Alternatively, the 2,5-dialkyl-4-tert-alkylphenol can be prepared from contacting 2,5-dialkylphenol with 2,2-dialkylethylene in the presence of an acid catalyst. An example of the alternative method is the incorporation of a tert-butyl group into the 4-position of 2,5-dialkylphenol by reacting 2,5-dialkylphenol with isobutylene in the presence of sulfuric acid.
In the second step of the process, 2,5-dialkyl-4-tert-alkylphenol can be oxidatively coupled using a copper diamine catalyst and oxygen as the oxidizing agent.
The copper diamine catalyst can be prepared using the procedure described in the Tetrahedron Letters, 1994, 35, 7983. A copper halide, such as CuCl, CuBr, CuI, or CuCl2, is added to a mixture of alcohol, such as methanol, and water and the diamine is slowly added. After the addition of the diamine, air is sparged through the mixture with vigorous stirring. The catalyst is filtered. Additional catalyst can be obtained by concentrating the filtrate and filtering the desired catalyst. The catalyst can also be prepared in situ by contacting the copper halide and the diamine in the solvent for the coupling reaction. Suitable solvents for the oxidative coupling of tri and tetrasubstituted phenols are methylene chloride and aromatic solvents such as xylene, benzene and toluene. Example of diamines include, but are not limited to, the following: N,N,Nxe2x80x2,Nxe2x80x2-tetraethylethylene diamine, N,N,Nxe2x80x2,Nxe2x80x2-tetraethyl-1,3-propanediamine, N,N,Nxe2x80x2,Nxe2x80x2-tetraethylmethane diamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-1,6-hexanediamine, N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl-1,3-propanediamine, dipiperidinomethane, N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene diamine and 1,4-diazabicyclo-(2,2,2)-octane. Preferrably, the diamine is N,N,Nxe2x80x2,Nxe2x80x2-tetramethylethylene diamine.
In the third step of the process, the 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-5,5xe2x80x2-di-tert-alkyl-2,2xe2x80x2-biphenol can be dealkylated by contacting it with a strongly acidic catalyst, such as an alkyl- or arylsulfonic acid, sulfuric acid, phosphoric acid, aluminum chloride, or the like, optionally in the presence of a solvent such as toluene, chlorobenzene, nitromethane, or xylene, typically at temperatures between 10 and 150xc2x0 C.
The oxidative coupling can be carried out neat (without a solvent) or using one or more of a wide range of poorly oxidizable solvents including dichloromethane, chlorobenzene, toluene, xylenes, nitromethane, paraffins, etc. Static air, air-flow, or oxygen can be used as oxidants in the oxidative coupling.
The third aspect of the present invention provides a process for making a compound of the formula I 
wherein
R1 is C1 to C10 primary or secondary alkyl or cycloalkyl,
R2 is C1 to C10 primary or secondary alkyl or cycloalkyl, and
X is H,
comprising:
(a) oxidatively coupling a compound of the formula III 
xe2x80x83wherein X is Cl, to produce a compound of the formula I wherein X is Cl, and
(b) dechlorinating the compound of the formula I wherein X is C to produce a compound of the formula I wherein X is H.
In the first step of the process, the resulting 2,5-dialkyl-4-chlorophenol can be oxidatively coupled to give the corresponding dimeric chlorophenols (5,5xe2x80x2-dichloro-3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol). The preferred method for oxidative coupling of the chlorinated phenols is by the use of an iron(III) salt, preferably ferric chloride, in a suitable polar, aprotic solvent such as dichloromethane or nitromethane, preferably nitromethane at temperature between 0xc2x0 C. and 60xc2x0 C., preferably about 35xc2x0 C. The product is isolated by dilution with water and filtration.
In the second step of the process, dechlorination of 5,5xe2x80x2-dichloro-3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols can be accomplished by hydrogenolytic reduction to provide the required 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols. The reduction is carried out in the presence of hydrogen gas, preferably at pressures between 1 and 50 atmospheres and temperature between 5xc2x0 and 80xc2x0 C., and a formate salt, such as sodium formate, and Raney(copyright) nickel or palladium catalyst such as palladium hydroxide on carbon. If a palladium catalyst is used, the reaction is generally carried out in a protic solvent such as methanol, containing 1.0 to 4.0 equivalents of an amine such as triethylamine to absorb the hydrogen chloride produced in the reaction.
In the first, second and third aspects of the present invention, a 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-5,5xe2x80x2-dihalo-2,2xe2x80x2-biphenol may be halogenated at the para positions of 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenol, as shown below, 
wherein R1 is C1 to C10 primary or secondary alkyl or cycloalkyl; R2 is C1 to C10 primary or secondary alkyl or cycloalkyl; and X is Cl, Br or I.
Addition of Br to 3,3xe2x80x2,6,6xe2x80x2-tetraalkyl-2,2xe2x80x2-biphenols can be accomplished by reaction of Br2 in a suitable solvent. Typical solvents for bromination are low polarity solvents such as chloroform, dichloromethane, carbon tetrachloride, and carbon disulfide. In some cases, aqueous bromine can be used. The preferred process is one carried out in a low polarity solvent. This reaction can be accomplished at xe2x88x9210xc2x0 C. to 50xc2x0 C., preferably at room tempearature.
The compounds which are produced by the processes of the present invention can be used as reactants to make phosphorous-containing ligands that are useful to make catalysts that, in turn, are useful in both hydrocyanation and hydroformylation reactions. Bidentate phosphite ligands are particularly useful.
Bidentate phosphite ligands can be prepared as described in U.S. Pat. No. 5,235,113 by contacting phosphorochloridites with the biphenol compounds made by the processes of the present invention. More recent U.S. Pat. Nos. 6,031,120 and 6,069,267, incorporated herein by reference, describe selective synthesis of bidentate phosphite ligands in which a phosphorochloridite is prepared in-situ from phosphorus trichloride and a phenol such as o-cresol and then treated in the same reaction vessel with an aromatic diol to give the bidentate phosphite ligand. The biphenols of the present invention are substituted for the aromatic diol.
The compounds which are produced by the processes of the present invention can be polymerized and then used as reactants to make phosphorous-containing ligands that are useful to make catalysts that, in turn, are useful in both hydrocyanation and hydroformylation reactions.
The compounds made by the processes of the present invention, in which X is H, can be used to make polymeric ligands by a process which comprises: (1) reacting the compounds made by the processes of the present invention, in which X is H, with a compound containing at least two benzyl chloride groups, in the presence of a Lewis acid catalyst, and (2) reacting the product of step (1) with at least one phosphorochloridite compound in the presence of an organic base. Preferably the Lewis acid catalyst is zinc chloride or aluminum chloride, and the organic base is a trialkylamine.
The compounds made by the processes of the present invention, in which X is Cl, Br, or I, can be used to make polymeric ligands by a process which comprises:
(1) protecting the OH groups by substituting a lower alkyl protecting group for H on the OH groups to make a protected compound,
(2) treating the protected compound with a compound containing at least two boronic groups in the presence of a Group VIII transition metal catalyst,
(3) replacing the protecting group of the product from step (2) with hydrogen, and
(4) reacting the product of step (3) with at least one phosphorochlorodite compound in the presence of an organic base.
Preferably, the Group VIII transition metal is palladium, nickel or copper and the organic base is a trialkylamine compound in which the alkyl group is a C1 to C12 branched or straight chain alkyl group. More preferably the organic base is triethylamine.
Two particularly important industrial catalytic reactions using phosphorus-containing ligands are olefin hydrocyanation and isomerization of branched nitrites to linear nitrites. See, for example, U.S. Pat. Nos. 5,512,695 and 5,512,696, and International Patent Application WO9514659. Phosphite ligands are particularly useful for both reactions. The hydrocyanation of unactivated and activated ethylenically unsaturated compounds (olefins) using transition metal complexes with monodentate and bidentate phosphite ligands is well known. Bidentate phosphinite and phosphonite ligands are useful as part of a catalyst system for the hydrocyanation of ethylenically unsaturated compounds. Bidentate phosphinite ligands are also useful as part of a catalyst system for the hydrocyanation of aromatic vinyl compounds.
Hydroformylation is another industrially useful process that utilizes catalysts made from phosphorus- containing ligands. The use of phosphine ligands, including diphosphines, is known for this purpose. The use of catalysts made from phosphite ligands is also known. Such catalysts usually contain a Group VIII metal. See for example, U.S. Pat. No. 5,235,113.
Two particularly useful compounds that can be made by the present processes are 3,3xe2x80x2,6,6xe2x80x2-tetramethyl-2,2xe2x80x2-biphenol and 3,3xe2x80x2-di-isopropyl-6,6xe2x80x2-dimentyl-2,2xe2x80x2-biphenol.